Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-19
2003-04-22
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06552040
ABSTRACT:
BACKGROUND OF THE INVENTION
The effects of ultraviolet radiation from exposure to the sun on human skin are a growing concern for today's longer-lived population. The majority of changes associated with an aged appearance result from chronic sun-damage (Warren et al.,
J. Am. Acad. Dermatol.,
1991, 25:751-760; Frances, C. and Robert, L.,
Int. J. Dermatol.,
1984, 23:166-179). Dramatic alterations of the superficial dermis accompany the deep wrinkles and laxity common in photoaged skin. The major histopathologic alteration of photoaged skin is the accumulation of material which, on routine histopathologic examination, has the staining characteristics of elastin and is, thus, termed solar elastosis. Immunohistochemical staining has shown the poorly-formed fibers comprising solar elastosis to be composed of elastin (Chen et al.,
J. Invest. Dermatol.,
1986, 87:334-337; Mera et al.,
Br. J. Dermatol.,
1987, 117:21-27) fibrillin (Chen et al.,
J. Invest. Dermatol.,
1986, 87:334-337; Dahlback et al.,
J. Invest. Dermatol.,
1990, 94:284-291; Bernstein et al.,
J. Invest. Dermatol.,
1994, 103:182-186) and versican, the normal components of elastic fibers (Zimmerman et al.,
J. Cell. Biol.,
1994, 124:817-825). A coordinate increase in elastin, fibrillin and versican mRNAs has been demonstrated in fibroblasts derived from photodamaged skin, as compared to fibroblasts derived from normal skin from the same individuals (Bernstein et al.,
J. Invest. Dermatol.,
1994, 103:182-186). Elevated elastin mRNA levels in sun-damaged skin result from enhanced elastin promoter activity, as shown by transient transfections of fibroblasts with a DNA construct composed of the human elastin promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene (Bernstein et al.,
J. Invest. Dermatol.,
1994, 103:182-186).
The generation of free radicals following exposure of the skin to ultraviolet radiation is well known in the art. Free radical mechanisms have been shown to be responsible for redness and erythema resulting from exposure to ultraviolet radiation. A number of antioxidants have been tested as photoprotective agents, however, results from these studies indicate that the ability of these agents to provide protection is variable.
Miyachi Y.,
J. Dermatol. Sci.
1995, 9:75-86 provides a review of photoaging from a photo-oxidative standpoint and suggests that use of antioxidants as regulators of photoaging. Specifically studies with superoxide dismutase (SOD) are described. However, it was concluded that sunscreen agents provided better protection from ultraviolet radiation.
Bissett et al.
Photodermatol. Photoimmunol. Photomed.
1990, 7:56-62 demonstrated that mice, topically treated with solutions of superoxide-scavenging anti-oxidants such as alphatocopherol, ascorbic acid, propyl galate and Trolox prior to ultraviolet B (UVB) radiation exposure, exhibited significantly less damage than untreated mice. However, additional antioxidants or free radical scavengers that were tested, including glutathione, beta-carotene, BHT, mannitol, divinylglycol, pantetheine, urea and histidine, provided no significant protection against UVB radiation. Further, the severity of UVA radiation-induced mouse skin damage was not reduced by topical application of these antioxidants in these studies. Thus, it is clear that the current approaches used to prevent the cumulative effect of photoaging are inadequate.
Historically, more research has been done in the area of radiation oncology. Damage from ionizing radiation and a portion of ultraviolet radiation-induced damage has been shown to be due to the formation of radical oxygen species. Sulfhydryl compounds were among the first radioprotectors to be identified. Their protective mechanism appears to be due to their ability to scavenge radiation-induced free radicals and/or donate reducing equivalents to oxidized molecules. hematopoietic cytokines have also been investigated as radioprotectors. They are believed to protect by more quickly restoring hematopoietic function after radiation exposure.
Recently, a new class of radioprotectors, referred to as nitroxides, has been described. As a class, nitroxides are stable free radical components which react with a variety of biologically relevant compounds including other free radicals (Nilsson et al.
J. Biol. Chem.,
1989, 264:11131-11135). The observation that several nitroxides themselves reacted with free radicals, specifically oxy radicals, led to the investigation of these compounds as radioprotectors (Saminu et al.
Free Radical Biol. Med.,
1989, 6:141-148).
Tempol [4-hydroxy-2,2,6,6-tetramethyl-piperidinyloxy, free radical] is a piperindinyl-n-oxyl with the n-oxide sterically stabilized by symmetric pairs of adjacent methyl groups. This compound is commercially available through Aldrich Chemical Co., Milwaukee, Wis. It is most commonly used to spin label biological molecules such as NADP.
Tempol has been demonstrated to function as a superoxide dismutase (SOD) mimic, protecting mammalian cells from superoxide generated from hypoxanthine/xanthine oxidase and from hydrogen peroxide mediated cytotoxicity (Mitchell et al.
Biochem.,
1990, 29:2802-2807; Samuni et al.,
J. Biol. Chem.,
1988, 263:17921-17924). Tempol has also been demonstrated to provide both in vitro and in vivo protection against ionizing radiation (Mitchell et al.
Arch. Biochem. Biophys.,
1991, 289:62-70) and to protect against radiation-induced alopecia by speeding the recovery of hair growth within a field of heavily irradiated skin (Goffman et al.
Int. J. Rad. Onc. Biol. Phys.,
1992, 22:803-806). This protection has been suggested to be linked to direct protection of hair follicle stem cells and development of other nitroxides.
U.S. Pat. No. 5,840,734 describes the use of Tempol in prevention of photoaging, sunburn and skin cancer caused by the UVA and UVB rays of sunlight.
It is now believed that topical application of nitroxide containing compounds other than Tempol will prevent photoaging, and other skin damage resulting from exposure to solar, and more specifically, ultraviolet radiation, such as sunburn and skin cancer. Further, topical application of nitroxide containing compounds is believed to be effective in promoting healing of acute and chronic wounds.
SUMMARY OF THE INVENTION
The present invention relates to a new use for nitroxide containing compounds. It is now believed that topical application of nitroxide containing compounds other than Tempol protects against photodamage including photoaging and other sun-damage such as sunburn and skin cancer caused by solar radiation. Further, it is believed that topical application of nitroxide containing compounds will also promote healing of acute and chronic wounds. Accordingly, nitroxide containing compounds are believed to be useful not only as sunscreen agents but also in wound healing. Thus, the present invention also relates to compositions comprising nitroxide containing compounds for use as sunscreen agents and in wound healing.
DETAILED DESCRIPTION OF THE INVENTION
Nitroxides are stable free radicals with antioxidant catalytic activities similar to superoxide dismutase. Nitroxides existing in vivo have been shown to interact with other substances to also mimic catalase activities. Thus, nitroxide containing compounds have been described in the art for numerous uses. For example, U.S. Pat. No. 5,462,946 discloses biologically compatible compositions containing an effective amount of a metal independent nitroxide compound for use in protecting the skin against ionizing radiation, mucositis, the effects of whole body radiation and radiation induced hair loss. In this embodiment, the nitroxide containing composition is applied topically as an ointment, lotion or cream, intravenously or orally by pill or lozenge. This patent also teaches the nitroxide containing compounds to be useful as protectants against: increased oxygen exposure so as to avoid pulmonary adult respiratory distress syndrome; oxygen-induced lenticular degeneration and hyaline memb
Henley III Raymond
Licata & Tyrrell P.C.
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